scholarly journals Cdr1p highlights the role of the non-hydrolytic ATP-binding site in driving drug translocation in asymmetric ABC pumps

2020 ◽  
Vol 1862 (2) ◽  
pp. 183131 ◽  
Author(s):  
Atanu Banerjee ◽  
Alexis Moreno ◽  
Mohammad Firoz Khan ◽  
Remya Nair ◽  
Suman Sharma ◽  
...  
Keyword(s):  
Binding Site ◽  
Atp Binding ◽  
Atp Binding Site

scholarly journals A Previously Unknown Unique Challenge for Inhibitors of SYK ATP-Binding Site: Role of SYK as A Cell Cycle Checkpoint Regulator

EBioMedicine ◽  
2014 ◽  
Vol 1 (1) ◽  
pp. 16-28 ◽  
Author(s):  
Fatih M. Uckun ◽  
Hong Ma ◽  
Zahide Ozer ◽  
Patricia Goodman ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Cell Cycle Checkpoint ◽  
Atp Binding ◽  
Unique Challenge ◽  
Atp Binding Site ◽  
Cycle Checkpoint ◽  
A Cell

scholarly journals Identification of Functional Amino Acids in the Macrolide 2′-Phosphotransferase II

1999 ◽  
Vol 43 (8) ◽  
pp. 2063-2065 ◽  
Author(s):  
Kazuo Taniguchi ◽  
Akio Nakamura ◽  
Kazue Tsurubuchi ◽  
Aki Ishii ◽  
Koji O’Hara ◽  
...  
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Site Directed Mutagenesis ◽  
Macrolide Antibiotics ◽  
Directed Mutagenesis ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Mutant Strains

ABSTRACT Macrolide 2′-phosphotransferase [MPH(2′)] transfers the γ phosphate of ATP to the 2′-OH group of macrolide antibiotics. The role of aspartic acids in the putative ATP-binding site of MPH(2′)II was investigated through the substitution of alanine for aspartate by site-directed mutagenesis. D200A, D209A, D219A, and D231A mutant strains were unable to inactivate the substrate oleandomycin, while a D227A mutant retained 7% of the activity of the original enzyme.

scholarly journals Role of the Glycine Triad in the ATP-binding Site of cAMP-dependent Protein Kinase

1997 ◽  
Vol 272 (27) ◽  
pp. 16946-16954 ◽  
Author(s):  
Wolfram Hemmer ◽  
Maria McGlone ◽  
Igor Tsigelny ◽  
Susan S. Taylor
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Atp Binding ◽  
Dependent Protein Kinase ◽  
Atp Binding Site ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Role of the ATP-binding site of SopA protein in partition of the F plasmid 1 1Edited by M. Yaniv

2001 ◽  
Vol 314 (3) ◽  
pp. 387-399 ◽  
Author(s):  
Virginie Libante ◽  
Laurent Thion ◽  
David Lane
Keyword(s):  
Binding Site ◽  
Atp Binding ◽  
F Plasmid ◽  
Atp Binding Site

New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations

2019 ◽  
Vol 19 (11) ◽  
pp. 914-926 ◽  
Author(s):  
Maiara Bernardes Marques ◽  
Michael González-Durruthy ◽  
Bruna Félix da Silva Nornberg ◽  
Bruno Rodrigues Oliveira ◽  
Daniela Volcan Almeida ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Cell Lines ◽  
Chemotherapeutic Agents ◽  
Atp Binding ◽  
Human Leukemia ◽  
Atp Binding Site ◽  
Mechanistic Insight ◽  
Multiple Drugs

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

scholarly journals Identification of the ATP binding site in tyrocidine synthetase 1 by selective modification with fluorescein 5'-isothiocyanate.

1994 ◽  
Vol 269 (21) ◽  
pp. 14962-14966
Author(s):  
M. Pavela-Vrancic ◽  
E. Pfeifer ◽  
W. Schröder ◽  
H. von Döhren ◽  
H. Kleinkauf
Keyword(s):  
Binding Site ◽  
Atp Binding ◽  
Atp Binding Site

scholarly journals Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K

2021 ◽  
Author(s):  
Afsar Ali Mian ◽  
Isabella Haberbosch ◽  
Hazem Khamaisie ◽  
Abed Agbarya ◽  
Larissa Pietsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Binding Pocket ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Lung Cancer Patients

AbstractResistance remains the major clinical challenge for the therapy of Philadelphia chromosome–positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common “gatekeeper” mutation T315I. Here we investigated the therapeutic potential of crizotinib, a TKI approved for targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also the ABL1 kinase in cell-free systems, for the treatment of advanced and therapy-resistant Ph+ leukemia. By inhibiting the BCR-ABL1 kinase, crizotinib efficiently suppressed growth of Ph+ cells without affecting growth of Ph− cells. It was also active in Ph+ patient-derived long-term cultures (PD-LTCs) independently of the responsiveness/resistance to other TKIs. The efficacy of crizotinib was confirmed in vivo in syngeneic mouse models of BCR-ABL1- or BCR-ABL1T315I-driven chronic myeloid leukemia–like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia.

scholarly journals Photoaffinity labelling of the ATP-binding site of the epidermal growth factor-dependent protein kinase

1984 ◽  
Vol 220 (3) ◽  
pp. 677-683 ◽  
Author(s):  
J E Kudlow ◽  
Y Leung
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Egf Receptor ◽  
Light Exposure ◽  
Atp Binding ◽  
Receptor Kinase ◽  
Dependent Protein Kinase ◽  
Atp Binding Site ◽  
Dependent Protein ◽  
Epidermal Growth

Epidermal growth factor (EGF), after binding to its receptor, activates a tyrosine-specific protein kinase which phosphorylates several substrates, including the EGF receptor itself. The effects of a photoaffinity analogue of ATP, 3′-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)adenosine 5′-triphosphate (arylazido-beta-alanyl-ATP) on the EGF-dependent protein kinase in A431 human tumour cell plasma membrane vesicles was investigated. This analogue was capable of inactivating the EGF-receptor kinase in a photodependent manner. Partial inactivation occurred at an analogue concentration of 1 microM and complete inactivation occurred at 10 microM when a 2 min light exposure was used. Arylazido-beta-alanine at 100 microM and ATP at 100 microM were incapable of inactivating the enzyme with 2 min of light exposure. The photodependent inactivation of the enzyme by the analogue could be partially blocked by 20 mM-ATP and more effectively blocked by either 20 mM-adenosine 5′-[beta gamma-imido]triphosphate or 20 mM-guanosine 5′-[beta gamma-imido]triphosphate, indicating nucleotide-binding site specificity. Arylazido-beta-alanyl-[alpha-32P]ATP was capable of labelling membrane proteins in a photodependent manner. Numerous proteins were labelled, the most prominent of which ran with an apparent Mr of 53000 on polyacrylamide-gel electrophoresis. A band of minor intensity was seen of Mr corresponding to the EGF receptor (170000). Immunoprecipitation of affinity-labelled and solubilized membranes with an anti-(EGF receptor) monoclonal antibody demonstrated that the Mr 170000 receptor protein was photoaffinity labelled by the analogue. The Mr 53000 peptide was not specifically bound by the anti-receptor antibody. The affinity labelling of the receptor was not enhanced by EGF, suggesting that EGF stimulation of the kinase activity does not result from changes in the affinity of the kinase for ATP. These studies demonstrate that arylazido-beta-alanyl-ATP interacts with the ATP-binding site of the EGF-receptor kinase with apparent high affinity and that this analogue is an effective photoaffinity label for the kinase. Furthermore, these studies demonstrate that the EGF receptor, identified by using monoclonal antibodies, contains an ATP-binding site, providing further confirmation that the EGF receptor and EGF-dependent protein kinase are domains of the Mr 170000 protein.

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